STUDIES TO EVALUATE THE POTENTIAL FOR ENVIRONMENTAL&THERAPEUTIC AGENTS TO INDUCE IMMUNOTOXICITY

评估环境潜力的研究

• 批准号: 9335709
• 负责人: Victor Johnson
• 金额: $ 370.37万
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-13 至 2017-08-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9335709
• 关键词: Adult; Affect; Animals; Antibody Response; Antigens; Aromatic Compounds; Autoimmune Diseases; Benzo(a)pyrene; Bone Marrow; Chemical Agents; Chemicals; Communicable Diseases; Complex Mixtures; Contracts; Control Groups; Cytology; Dermal; Development; Dose; Event; Exposure to; Food Additives; Health; Health Hazards; Hematopoietic; Human; Hypersensitivity; Immune system; Immunologic Techniques; Immunotoxicology; In Vitro; Individual; Inhalation Exposure; Laboratories; Life; Measures; Methods; Molecular; Mus; National Toxicology Program; Neoplasms; Oral; Pharmaceutical Preparations; Predictive Value; Protocols documentation; Pyrenes; Rattus; Reporting; Research; Resistance; Sampling; Severities; Site; Sodium; Structure; Testing; Therapeutic Agents; Toxic effect; Work; Xenobiotics; carcinogenicity; contaminated drinking water; dermal exposure; developmental toxicity; dietary supplements; emerging adult; environmental agent; exposed human population; immune function; immunotoxicity; in vivo; indexing; irritation; lymph nodes; lymphocyte proliferation; multi walled carbon nanotube; neurotoxicity; phenanthrene; programs; reproductive toxicity; respiratory; response; screening; skin irritation

Studies to investigate the potential for 4-Methylcyclohexanemethanol (MCHM) to induce dermal sensitization were completed and reported in FY16. Dermal exposure to pure MCHM was found to produce irritation of the skin at the application site at concentrations above 20% and overt toxicity at the 100% concentration, but did not induce sensitization. Mice treated with ≥75% crude MCHM also showed evidence of dermal irritation, although weaker when compared to pure MCHM. There was also evidence of overt toxicity in mice treated with 100% crude MCHM, although the severity was less than pure MCHM. Dermal application of crude MCHM resulted in increased lymphocyte proliferation in the draining lymph node at concentrations ≥5%. The Stimulation Index (SI), a measure of sensitization, was significantly increased in mice treated with ≥20% crude MCHM, relative to the vehicle control group. These results indicate that crude MCHM has the potential to cause dermal sensitization at exposure concentrations that are non-irritating. The PAC Mixtures Assessment Program (PAC-MAP) provides the framework for assessing a breadth of individual polycyclic aromatic compounds (PACs), defined PAC mixtures, and complex PAC-containing environmental samples using an in vitro/short-term in vivo testing battery that includes a broad spectrum of endpoints. Select PACs have been associated with a wide range of toxicities (carcinogenicity, immunotoxicity, reproductive and developmental toxicity, neurotoxicity) and a complicated array of mechanisms of action. In particular, many PACs have been associated with suppression of humoral immune function and immunotoxicity has been identified as an informative parameter for estimating the carcinogenic potential of PACs. As part of the potential testing battery to predict mixture effects, we have examined the potential for individual PACs to modulate the antigen specific antibody response and affect bone marrow cytology. Dose response studies for the positive control Benzo(a)pyrene and the less potent PAC, Phenanthrene have been completed and draft reports received for both studies. Laboratory protocols for three additional compounds, pyrene, dibenzothiophene and acenaphthenequinone, have been approved and the in life studies are expected to be completed in Q1FY17. The in-life portion of an assessment of the potential immunotoxicity oral exposure to the groundwater contaminant sulfolane has been completed in adult mice and rats exposed throughout development and early adulthood. Screening studies to assess immune function following exposure to the drinking water contaminate sodium metavanadate have also been completed. Draft reports for these studies are expected in Q1FY17. Two sets of immunotoxicity studies, conducted in B6C3F1/N mice and HSD rats following 30-day inhalation exposures to multi walled carbon nanotubes have been completed and the in life work for a third study, with an exposure duration of 90 days, is ongoing.

在2016财年中，完成并报告了研究4-甲基环己氨甲醇（MCHM）诱导皮肤敏感性的潜力。发现皮肤暴露于纯MCHM上，以高于20％的浓度和100％浓度的明显毒性引起皮肤的刺激，但不会引起敏感性。用≥75％粗MCHM处理的小鼠也显示出皮肤刺激的证据，尽管与纯MCHM相比较弱。也有证据表明用100％粗MCHM处理的小鼠明显毒性，尽管严重程度小于纯MCHM。原油MCHM的皮肤应用导致浓度≥5％的排水淋巴结中淋巴细胞增殖增加。相对于车辆对照组，用≥20％粗MCHM处理的小鼠的刺激指数（Si）显着增加了敏感性。这些结果表明，在暴露浓度的情况下，粗MCHM有可能引起皮肤敏感性。 PAC混合物评估计划（PAC-MAP）提供了评估单个多环芳族化合物（PACS），定义的PAC混合物和复杂含PAC PAC的环境样品的框架，该框架使用体外/短期内体内测试电池，其中包括广泛的端点。精选的PACS与广泛的毒性（致癌性，免疫毒性，生殖和发展毒性，神经毒性）和复杂的作用机理有关。特别是，许多PAC与抑制体液免疫功能相关，并且已经将免疫毒性确定为估计PAC的致癌潜力的信息参数。作为预测混合物效应的潜在测试电池的一部分，我们检查了单个PAC调节抗原特异性抗体反应并影响骨髓细胞学的潜力。阳性对照苯并（a）pyrene和潜在的PAC，菲人的剂量反应研究已经完成，并收到了两项研究的报告草案。已批准了三种其他化合物，pyrene，dibenzothiophene和achephenequinone的实验室方案，预计生命研究将在2017年第17季度完成。评估潜在的免疫毒性口腔暴露于地下水污染物磺烷的生命部分已在成年小鼠和整个发育和成年早期暴露的成年小鼠和大鼠中完成。筛查研究以评估暴露于饮用水后的免疫学功能，也已完成污染Metavanate钠。这些研究的报告预计在2017年第17季度。 30天吸入暴露于多壁碳纳米管后，在B6C3F1/N小鼠和HSD大鼠中进行的两组免疫毒性研究已经完成，第三次研究的生活工作是90天的第三次研究。